Studies on the immunologic mechanisms of susceptibility and resistance to street rabies virus (SRV) in mice are still being pursued using a model system developed by Dr. Donald Lodmell of LPVD. Previous investigations by my lab revealed that infection of susceptible mice is accompanied by severe involution of the immune system due to an adrenal stress response with excessive secretion of lymphotoxic corticosteroids. Further experiments revealed that starvation induced stress could not account for adrenal hyperactivity and that virus infection of the pituitary gland is a more likely explanation for adrenal dysfunction. Lymphoid involution appears to be a consequence rather than a cause of susceptibility to SRV in mice. These results have been published in the Journal of Immunology (144:3552-3557, 1990). The contribution of the peritoneal inflammatory response to rabies resistance was also investigated. Mice of susceptible strains (A strain mice) are known to have a number of defects in macrophage activation and chemotaxis that render them susceptible to a variety of bacterial infections. In our studies, peritoneal inflammatory responses were shown to be much greater in resistant as compared to susceptible strains of mice coupled with more rapid clearance of virus from the peritoneum. Induction of macrophage infiltrates in susceptible mice by pretreatment with trehalose dimycolate, the active component of an adjuvant under development for human use by Ribi Laboratories, induces protection in 60% of infected animals. Treatment is associated with an increase in peritoneal macrophages but not with increased anti-rabies antibody reactivity, suggesting that the early inflammatory response provides one level of protection against rabies lethality. Finally, the mechanism of rabies resistance in SJL and BALB/C mice has been investigated by in vivo depletion of Th and Tc subsets using monoclonal antibodies. SJL mice apparently eliminate rabies virus in the periphery prior to penetration of the CNS, while BALB/c mice develop a CNS infection which they subsequently clear immunologically. Depletion of Th but not Tc cells reverses the resistance of SJL mice indicating a predominant role for antibody in virus elimination outside of the CNS. Depletion of Tc in BALB/C mice also results in complete susceptibility to virus lethality. Interestingly, depletion of Tc in BALB/C but not SJL mice also results in ultimate susceptibility to rabies disease, apparently due to a failure to clear virus infection within the CNS. This is the first direct evidence for a role of Tc in elimination of rabies infection within the CNS.